NMDA receptor agonist pharmaceutical compositions

ABSTRACT

This invention relates to stable pharmaceutical compositions of the NMDA receptor agonist, (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol], methods of preparing such pharmaceutical compositions and methods of treating stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, CNS degenerative diseases such as Alzheimer&#39;s disease, senile dementia of the Alzheimer&#39;s type, Huntington&#39;s disease, Parkinson&#39;s disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychotic conditions, drug addictions, migraine, hypoglycemia, anxiolytic conditions, urinary incontinence and an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised using the pharmaceutical compositions.

BACKGROUND OF THE INVENTION

[0001] This invention provides stable pharmaceutical compositions of theN-methyl-D-aspartic acid (NMDA) receptor antagonist,(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol,methods of preparing such pharmaceutical compositions and methods oftreating stroke, spinal cord trauma, traumatic brain injury,multiinfarct dementia, CNS degenerative diseases such as Alzheimer'sdisease, senile dementia of the Alzheimer's type, Huntington's disease,Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDSdementia, psychotic conditions, drug addictions, migraine, hypoglycemia,anxiolytic conditions, urinary incontinence and an ischemic eventarising from CNS surgery, open heart surgery or any procedure duringwhich the function of the cardiovascular system is compromised, usingthe pharmaceutical compositions of this invention.

[0002](1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy4-phenylpiperidin-1-yl)-1-propanol(hereafter referred to as the “Compound”) is a neuroprotecting agentthat is useful for the treatment of stroke, spinal cord trauma,traumatic brain injury, multiinfarct dementia, CNS degenerative diseasessuch as Alzheimer's disease, senile dementia of the Alzheimer's type,Huntington's disease, Parkinson's disease, epilepsy, amyotrophic lateralsclerosis, pain, AIDS dementia, psychotic conditions, drug addictions,migraine, hypoglycemia, anxiolytic conditions, urinary incontinence andan ischemic event arising from CNS surgery, open heart surgery or anyprocedure during which the function of the cardiovascular system iscompromised. The Compound exhibits activity as an NMDA receptorantagonist. NMDA is an excitatory amino acid involved in excitatoryneurotransmission in the central nervous system. NMDA antagonists arecompounds that block the NMDA receptor by interacting with thereceptor's binding site.

[0003] Antagonists of neurotransmission at NMDA receptors are usefultherapeutic agents for the treatment of neurological disorders. U.S.Pat. No. 4,902,695 is directed to series of competitive NMDA antagonistsuseful for the treatment of neurological disorders, including epilepsy,stroke, anxiety, cerebral ischemia, muscular spasms, andneurodegenerative disorders such as Alzheimer's disease and Huntington'sdisease. U.S. Pat. No. 4,968,878 is directed to a second series ofcompetitive NMDA receptor antagonists useful for the treatment ofsimilar neurological disorders and neurodegenerative disorders. U.S.Pat. No. 5,192,751 discloses a method of treating urinary incontinencein a mammal, which comprises administering an effective amount of acompetitive NMDA antagonist.

[0004] Commonly assigned U.S. Pat. No. 5,272,160 and commonly assignedU.S. Pat. No. 5,710,168 (the disclosures of which are herebyincorporated by reference) disclose the Compound and methods of usingthe Compound for treatment of diseases or conditions that aresusceptible to treatment by blocking NMDA receptor sites, includingstroke, spinal cord trauma, traumatic brain injury, multiinfarctdementia, CNS degenerative diseases, epilepsy, amyotrophic lateralsclerosis, pain, AIDS dementia, psychotic conditions, drug addictions,migraine, hypoglycemia, anxiolytic conditions, urinary incontinence andischemic events.

[0005] Commonly assigned U.S. Pat. No. 6,008,233 (the disclosure ofwhich is hereby incorporated by reference) discloses themethanesulfonate trihydrate of the Compound and uses thereof fortreatment of the aforesaid diseases and conditions.

[0006] The Compound is preferably administered as an intravenousinfusion lasting many hours. Such administration is intended to maintaina desired blood level of the compound for the duration of the therapy.Typically, therapy with the Compound is initiated in the hospitalemergency room and continues for a desired time in the ICU or othercritical care units.

[0007] Formulations and dosage presentations of the Compound should bedesigned for convenient and efficient administration and should beespecially suited for the emergency setting. Degradation of the Compoundin such formulations should be minimized.

SUMMARY OF THE INVENTION

[0008] This invention provides relatively stable formulations of theCompound in aqueous solutions made by reducing or removing the presenceof trace metal ions in the solutions. Stability is further improvedthrough the use of a pharmaceutically acceptable buffer. Additionalstability is afforded by reducing the presence of oxygen in theformulations.

[0009] One aspect of the present invention is pharmaceuticalcompositions comprising a pharmaceutically effective amount of(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanolor a pharmaceutically acceptable salt thereof and water, wherein saidcompositions contain less than about 2 parts per million of free copperion and less than about 2 parts per million of free iron ion.

[0010] Another aspect of the present invention is pharmaceuticalcompositions comprising(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanolor a pharmaceutically acceptable salt thereof, water and apharmaceutically acceptable chelating agent, preferablyethylenediaminetetraacetic acid, citric acid, succinic acid or tartricacid or a pharmaceutically acceptable salt thereof, at a concentrationeffective to chelate with trace metal ions present in said composition.

[0011] A further aspect of the present invention is pharmaceuticalcompositions comprising(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanolor a pharmaceutically acceptable salt thereof in an aqueous solution,wherein the percent of the degradation product, 4-hydroxybenzaldehyde,is no more than about 0.15 percent of said composition following storageat 50° C. for 12 weeks, preferably no more than about 0.07 percent andmost preferably no more than about 0.04 percent.

[0012] An additional aspect of this invention is pharmaceuticalcompositions comprising(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy4-phenylpiperidin-1-yl)-1-propanolor a pharmaceutically acceptable salt thereof in an aqueous solution,wherein the percent of the degradation product,4-hydroxy-4-phenylpiperidine, is no more than about 0.2 percent of saidcomposition following storage at 50° C. for 12 weeks, preferably no morethan about 0.1 percent and most preferably no more than about 0.05percent.

[0013] An additional aspect of this invention is methods of treatingstroke, spinal cord trauma, traumatic brain injury, multiinfarctdementia, CNS degenerative diseases such as Alzheimer's disease, seniledementia of the Alzheimer's type, Huntington's disease, Parkinson'sdisease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia,psychotic conditions, drug addictions, migraine, hypoglycemia,anxiolytic conditions, urinary incontinence and an ischemic eventarising from CNS surgery, open heart surgery or any procedure duringwhich the function of the cardiovascular system is compromised, inmammals, comprising administering to a mammal in need of such treatmenta pharmaceutical composition of this invention.

[0014] In a preferred embodiment of the composition aspects of thisinvention, the compositions are substantially free of free copper ionand free iron ion.

[0015] In another preferred embodiment of the composition aspects ofthis invention, the compositions contains less than about 2 parts permillion of any free trace metal ion, and more preferably issubstantially free of any free trace metal ion.

[0016] Another preferred embodiment of the composition aspects of thisinvention provides that the compositions comprise a pharmaceuticallyacceptable buffer at a concentration effective to maintain the pH of thecompositions at between about 3.8 to about 5.0 and more preferably atbetween about 4.0 to about 4.5. In a more preferred embodiment, theanion of the buffer is selected from acetate, citrate, tartrate, formateand lactate, most preferably lactate.

[0017] A further preferred embodiment of the composition aspects of thisinvention provides that the compositions are substantially free ofoxygen.

[0018] In a preferred embodiment of the method of treatment aspects ofthis invention, the mammal is a human.

[0019] The term “chelating agent” as used herein means any compound thatsequesters, forms a complex or otherwise interacts with trace metal ionssuch that the destabilizing effect of such metal ions to the Compound inaqueous solution is minimized. Exemplary chelating agents includeethylenediaminetetra-acedic acid (EDTA) and its salts,trans-1,2-diaminocyclohexanetetra-acedic acid (DCTA) and its salts,bis-(2-aminoethyl)ethyleneglycol-NNN′N′-tetraacetic acid (EGTA) and itssalts, diethyllenetriamineepenta-acetic acid (DTPA) and its salts,tri-(2-aminoethyl)amine (tren),NNN′N′-tetra-(2-aminoethyl)ethylenediamine (penten), nitrilotriacedicacid (NTA) and its salts, 2,3-dimercapto-1-propanesulfonic acid (DMPS)and its salts, meso-2,3-dimercaptosuccinnic acid (DMSA) and its salts,hydroxyl acids such as citric, tartaric, lactic, succinic, etc. andtheir salts, and certain amino acids such as glycine, histidine, andglutamic acid and their salts.

[0020] The term “Degradant 1” as used herein refers to the degradationproduct of the Compound, 4-hydroxybenzaldehyde.

[0021] The term “Degradant 2” as used herein refers to the degradationproduct of the Compound, 4-hydroxy-4-phenylpiperidine.

[0022] The terms “free copper ion”, “free iron ion” and “free tracemetal ion” as used herein means copper ions, iron ions or trace metalions, respectively, that when present in an aqueous compositioncomprising the Compound are in a form or state as to enable them tocause, initiate, encourage or catalyze degradation of the Compound.

[0023] “Headspace” refers to the difference in volume between a closedcontainer (e.g., a vial) and the volume of liquid contained in thatcontainer. The headspace can be quantified as a percent of the totalvolume of the closed container.

[0024] The expression “means to remove trace metal ions” as used hereinmeans any means that may be used to remove trace metal ions from anaqueous solution. For example, such means can include the use of metalchelating resins or other chelating reagents that are known to thoseskilled in the art.

[0025] The term “non-reactive gas” as used herein means any gas thatdoes not react or interact chemically with a pharmaceutical compositionor any of its components. Such gas is preferably nitrogen, but may beargon, helium, or any other gas known by those skilled in the art forits non-reactive properties.

[0026] The expressions “percent of Degradant 1” and “percent ofDegradant 2” means the percent of the applicable degradation productpresent in a pharmaceutical composition of the Compound in weight versusweight (w/w) terms. The percent is calculated from peak areas derivedfrom HPLC analysis according to the formula:

Percent of Degradant=[(A _(SAMP) ×D _(SAMP))/(R _(AVG) ×C _(LAB))]×100

[0027] where:

[0028] A_(SAMP)=impurity peak area

[0029] D_(SAMP)=dilution factor, calculated as:

D_(SAMP)=C_(LAB)/C_(SAMP)

[0030] where:

[0031] C_(LAB)=label concentration of the Compound in the formulationbeing-tested (free base concentration)

[0032] C_(SAMP)=concentration of the free base of the Compound in thesample tested (based upon dilution of the label concentration used tomake the sample)

[0033] R_(AVG)=is the average standard response factor (“R”) obtainedfrom analysis of a standard solution, calculated as:

R=A _(STD)/(C _(STD) ×PF)

[0034] where:

[0035] A_(STD)=peak area of the Compound in the standard solution

[0036] C_(STD)=concentration of the Compound in the standard solution

[0037] PF=potency factor of the Compound in the standard solution,calculated as the molar weight of the free base of the compound dividedby the molar weight of the actual compound in the standard solution.

[0038] The dilution factor, D_(SAMP), accounts for dilution that may benecessary so that the sample tested is within the validatedconcentration limits of the HPLC method.

[0039] The expression “pharmaceutically acceptable” as used hereinrefers to carriers, diluents, excipients, buffers and/or salts that arecompatible with the other ingredients of the formulation and are notdeleterious to the recipient thereof.

[0040] The term “substantially free” as used herein with respect to thepresence of trace metal ions in pharmaceutical compositions comprisingthe Compound, means a quantity that is less than that which would have asubstantial effect on degradation of the Compound in such compositions.Notwithstanding the foregoing, such an amount is less than about 2 ppmfor any applicable trace metal ion. The term “substantially free” asused herein with respect to the presence of oxygen in or in contact withpharmaceutical compositions comprising the Compound, means a quantity ofoxygen that is less than that which would have a substantial effect ondegradation of the Compound in such compositions. For example, incompositions packaged in closed containers or vials having a headspacewherein such headspace is 25% or less of the volume of the container orvial, the term “substantially free” means that there is less than 10%oxygen in such headspace.

[0041] The term “trace metal ion” as used herein means any metal ionthat, when present in an aqueous pharmaceutical composition comprisingthe Compound, causes, initiates, encourages or catalyzes degradation ofthe Compound, especially ions of transition metals and most especiallyiron and copper ions.

DETAILED DESCRIPTION OF THE INVENTION

[0042] The active ingredient in the present pharmaceutical compositionsis(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol,which may be present as its free base or as a pharmaceuticallyacceptable salt, preferably the methanesulfonate (mesylate) salt. Thepreparation of(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanolis described in U.S. Pat. No. 5,272,160 and in U.S. Pat. No. 6,008,233.The preparation of the mesylate salt trihydrate is described in U.S.Pat. No. 6,008,233.

[0043] In a representative example,(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanolis administered to a stroke or head trauma patient at the emergency siteor in the hospital emergency room by intravenous infusion. Therapy wouldcontinue in the ICU or other critical care units. The amount of thecompound to be administered would, in part, depend on the body weight ofthe patient.

[0044] A concentrated solution of(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanolthat can readily be diluted according to the needs of the patientprovides the required dosing flexibility. The concentrated solutionwould, if necessary, be diluted to the appropriate concentration foradministration to the patient.

[0045] Formulations of the present pharmaceutical compositions may be inthe form of concentrated solutions intended to be diluted in a suitableIV diluent prior to administration. The formulations may also beprepared as ready to use forms that are at concentrations that can beadministered without further dilution. The preferred concentration ofthe compositions in concentrate form is 10 milligrams of the free baseof the active compound,(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol,per 1 milliliter of solution (i.e., 10 mgA/mL). The preferredconcentration of the ready to use forms is 1.25 mgA/mL.

[0046] The composition is administered full strength or is diluted asrequired. A preferred dosage concentration for administration to thepatient is 0.1 mgA/mL to 10 mgA/mL. A more preferred dosage foradministration is at a concentration of 0.5 mgA/mL to 2.0 mgA/mL. Aneven more preferred dosage concentration is 1.25 mgA/mL. The preferredIV diluent of the composition is normal saline solution (0.9% NaCl).

[0047] Two degradants produced by the chemical degradation of(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanolin aqueous solutions are the compounds 4-hydroxybenzaldehyde (hereafter“Degradant 1”) and 4-hydroxy-4-phenylpiperidine (hereafter “Degradant2”). While not essential to the practice of this invention and notintending to be limited in any manner thereby, it is believed that suchdegradation is the result of oxidation of(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol.

[0048] Trace metal ion contamination has been found to be a criticalfactor in the degradation of the Compound. Such effects are exemplifiedby spiking experiments of solutions containing the Compound with iron orcopper ions. Table 1 shows the effect of iron and copper ions inunbuffered water for injection (WFI) solution on degradation productformation. TABLE 1 Effect of Fe²⁺ and Cu⁺ spiking on degradation of theCompound. Numbers represent percent of Degradant 1 (w/w). Days at 70° C.WFI only Fe²⁺ (20 ppm) Cu⁺ (20 ppm) Day 0 0.002% 0.024% 0.085% Day 30.007% 0.061% 0.107% Day 7 0.009% 0.110% 0.128%

[0049] An, effective, means of improving the chemical stability of theCompound is achieved by removing trace metal ions from the aqueousformulation. One method of metal ion removal is by employing agentsspecifically designed for this purpose. Exemplary metal ion removingagents include chelating resins such as Chelex® (Chelex is a trademarkof Bio-Rad Laboratories, Inc., Hercules, Calif.). However, otherpharmaceutically acceptable chelating resins or reagents performing thesame function would be acceptable so long as they do not detrimentallyaffect the Compound or other components of the formulation.

[0050] Treatment for removal of trace metal ions may be performed onindividual components of the formulation prior to final formulation orsuch treatment may be performed on the formulation itself. For example,water that is to be used in the formulation may be treated to removetrace metals. Alternatively, concentrated buffer solutions may betreated prior to dilution with water and formulation with the activeingredient. In another alternative, the aqueous solution containing allcomponents of the formulation except for the active pharmaceuticalingredient may be treated to remove metal ions. A still furtheralternative is to treat the complete formulation that contains allcomponents, including the active ingredient.

[0051] An alternative to removal of trace metal ions is to incorporatecertain compounds in the formulation that will form a chelate with thetrace metal ions, thereby minimizing their degradation effect. Examplesof such chelating agents include ethylenediaminetetraacetic acid (EDTA)disodium and citrate and tartrate buffers. The preferred concentrationof EDTA disodium, citrate buffer and tartrate buffer is 10 mM each.Citrate and tartrate are believed to act as chelating agents for tracemetal ions. In addition, succinate is believed to act as a chelatingagent. Other chelating agents will be apparent to those skilled in theart in light of this disclosure.

[0052] Aqueous solutions of the Compound are susceptible to pH shift.The compound is believed to exhibit its best chemical stability betweenpH 4.0 and 4.5. When the Compound is formulated with only water, the pHof the formulation increases above 5. This pH shift results inconditions favorable to the oxidative degradation reaction, thusaccelerating the degradation of the aqueous formulation. The increase inpH also decreases the solubility of the compound, thereby increasing thepossibility of precipitation out of solution.

[0053] The pH shift may be minimized by using a suitable buffer. Thoseskilled in the art will appreciate that any pharmaceutically acceptablebuffer that maintains the pH of the formulation within a certain rangemay be used. The pH range of such buffer is preferably between about 3.8and about 5.0, and most preferably between 4.0 and 4.5. Suitable buffersinclude, but are not limited to, acetate, benzoate, citrate, formate,lactate and tartrate buffers, preferably lactate.

[0054] Table 2 exemplifies the use of various buffers to stabilize thepH of formulations containing 10 mgA/ml of the Compound. TABLE 2 pH at70° C. Initial Buffer lot (post-TS) 2 days 4 days 7 days 21 days 10 mMacetate 4.16 N/T 4.14 4.14 4.17 10 mM benzoate 4.21 N/T 4.16 4.20 N/A 10mM citrate 4.16 4.16 N/T 4.17 4.11 10 mM formate 4.17 4.18 N/T 4.16 4.13 3 mM lactate 4.24 4.21 N/T 4.20 4.14 10 mM tartrate 4.15 4.17 N/T 4.174.07

[0055] In order to further improve stability of the active compound, itis preferable that the oxygen content in the formulation be reduced.This can be done by sparging the formulation solution with nitrogen,argon or other non-reactive gas and, when the compositions of theinvention are packaged in vials or similar containers containing aheadspace, using such inert gas for the headspace. When the compositionsof the invention are packaged so that they contain a headspace, it ispreferable that the oxygen content in the headspace be less than about12% and most preferably less than about 8%. Oxygen may be removed byother methods, including the use of a vacuum to remove air and oxygen.Other methods of oxygen removal will be apparent to those skilled in theart.

[0056] A preferred presentation of the composition aspects of theinvention comprises the Compound at a concentration of 10 mgA/mL. Thisconcentration is near the maximum solubility of the Compound (about 12mgA/mL at 5° C.). The preferred solution of the composition is 10 mMlactate buffer. However, those skilled in the art will appreciate thatbuffer solutions of other anions may be used, including, but not limitedto, buffer solutions of the anions acetate, citrate, tartrate andformate.

[0057] A preferred packaging of the compositions is a 40 cc, Flint TypeI molded glass vial with rubber stopper and aluminum shell. Alternativepresentations can include other vial or container types, pre-filledsyringes or pre-filled IV bags. Other packaging presentations will beapparent to those skilled in the art.

[0058] Vials are preferably sterilized by terminal sterilization methodsemploying an autoclave. Preferably, sterilization is for 8 minutes at121° C. Sterilization may cause a slight shift of pH. In the lactatebuffered formulation, pH shifted slightly down. In order to achieve amid-point in the preferred pH range, the initial pH is preferably set to4.5. The terminal sterilization cycle reduces the pH to about 4.2.

EXPERIMENTAL EXAMPLES

[0059] The present invention is illustrated by the following examples,but is not limited to the details thereof.

[0060] Percentages of Degradant 1 and Degradant 2 where measured usingreverse-phase HPLC analysis on a Kromasil® C4 column, 5 μm, 25 cmlength×4.6 mm ID (EKA Chemicals, Bohus Sweden). Column temperature was30° C.±5° C. Mobile phase A: water/acetonitrile/trifluoracetic acid,90/10/0.1 (v/v/v). Mobile phase B: water/acetonitrile/trifluoraceticacid, 40/60/0.1 (v/v/v). Gradient profile: linear. Detection: UV @215nm. Flow rate: 1.5 mL/min. Injection volume: 10 μL.

Example 1

[0061] Effect of Treatment with a Chelating Resin.

[0062] Solutions of sodium chloride of 0.3, 0.6 and 0.9% were treatedwith 5% w/w of Chelex® resin and stirred slowly for 1 hour. The pH ofthe solutions was adjusted to 4.6 while stirring with the Chelex resin.The mixture was then filtered. Control samples of sodium chloridesolutions of 0.3, 0.6 and 0.9% were prepared which were not treated withthe Chelex resin. Treated and untreated solutions were combined with(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanolat a concentration of 1.25 mgA/ml and stored in sealed 5 cc Flint type Imolded vials containing 4.0 ml solution fill and 2.0 ml air headspace at70° C. for 7 days. The results of this experiment are represented inTable 3. TABLE 3 Numbers represent percent of Degradant 1 (w/w). % NaClUntreated Treated 0.3 0.034% 0.004% 0.6 0.038% 0.003% 0.9 0.033% 0.003%

Example 2

[0063] Effect of Formulating with a Chelating Agent.

[0064] The following solutions were made to a concentration of 10 mMeach at pH 4.2:

[0065] 1. Unbuffered normal saline (0.9% NaCl);

[0066] 2. 10 mM Citrate buffer in normal saline (0.9% NaCl);

[0067] 3. 10 mM Tartrate buffer in normal saline (0.9% NaCl); and

[0068] 4. 10 mM EDTA disodium in normal saline (0.9% NaCl);

[0069] Solutions of each were combined with(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanolto a concentration of 1.25 mgA/ml and the pH was adjusted to 4.2. Eachformulation was subjected to an 8 minute autoclave cycle at 121° C. andthen stored at 70° C. The results of this experiment are represented inTable 4 below. TABLE 4 Numbers represent percent of Degradant 1 (w/w).0.9% NaCl 10 mM 10 mM 10 mM Saline Tartrate Citrate EDTA Day 0 N/A0.002% 0.000% 0.000% Day 3 N/A 0.003% 0.001% 0.000% Day 7 0.033% 0.006%0.001% 0.002%

Example 3

[0070] 4-Hydroxybenzaldehyde (Degradant 1).

[0071] NMR analysis was performed at ambient temperature on a BrukerAvance DRX 500 MHz NMR spectrometer using a Bruker 5mm gradientbroadband inverse probe (Bruker Instruments, Inc., Billerica, Mass.).Sample was dissolved in 99.9% deuterated dimethyl sulfoxide (DMSO).¹³C-NMR ¹H-NMR Carbon (PPM) H's Attached Proton (PPM) δ ProtonMultiplicity 115.84 1 6.92 doublet 128.43 0 132.10 1 7.74 Doublet 163.320 190.95 1 9.77 Singlet

Example 4

[0072] 4-Hydroxy-4-phenylpiperidine (Degradant 2).

[0073] NMR analysis was performed at ambient temperature on a BrukerAvance DRX 500 MHz NMR spectrometer using a Bruker 5 mm gradientbroadband inverse probe. Sample was dissolved in 99.9% deuterateddimethyl sulfoxide (DMSO). ¹³C-NMR ¹H-NMR Carbon (PPM) H's AttachedProton (PPM) δ Proton Multiplicity 39.05 2 1.49 doublet 1.77 triplet42.03 2 2.70 doublet 2.92 triplet 70.41 0 124.70 1 7.46 doublet 125.97 17.18 triplet 127.76 1 7.30 triplet 150.76 0

Example 5

[0074] Formulation of(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanolin lactate buffer. Weight Concentration Component Grade Function(mg/vial) (mg/ml) (1S,2S)-1-(4- Pharm Active 586.01 14.577hydroxyphenyl)-2- ingredient (equal to (4-hydroxy-4- 10 mgA/ml)phenylpiperidin-1- yl)-1-propanol mesylate trihydrate Lactic Acid USPBuffer 41.12 1.023 Sodium Hydroxide NF pH modifier Ca 13.87 Ca 0.345Hydrochloric Acid NF pH modifier 0 0 Water for Injection USP Vehicle39711.76 987.855

[0075] USP=United States Pharmacopoeia

[0076] NF=National Formulary

[0077] The pH of the initial formulation is set at pH 4.5 to accommodatethe slight pH down-shifting upon terminal sterilization. The terminalsterilization cycle lowers the pH to about 4.2. Sodium hydroxide andhydrochloric acid are used as needed to adjust the solution to thedesired pH.

Example 6

[0078] Accelerated Stability Study.

[0079] A-10 mgA/ml solution of(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanolin 10 mM lactate buffer was prepared. The pH of three separate portionswas adjusted so that the initial post terminal sterilization pH was 3.9,4.2 or 4.6. The formulation was packaged in vials containing varyingconcentrations of oxygen or in air. Terminal sterilization was byautoclave at 121° C. for 8 minutes. Samples were stored in 40 ml Flinttype I vials with 40 ml fill and 10 ml headspace for 12 weeks at 30° C.,40° C. and 50° C.

[0080] The results of this experiment are presented in Table 5 and Table6 below. TABLE 5 Numbers represent percent of Degradant 1 (w/w). Headspace, pH Initial Post T.S. 30° C. 40° C. 50° C.  4% O₂, pH 4.2 0.002%0.004% 0.003% 0.005% 0.009%  6% O₂, pH 4.2 0.002% 0.004% 0.004% 0.005%0.011% 10% O₂, pH 4.2 0.004% 0.003% 0.004% 0.006% 0.015% Air, pH 4.60.003% 0.003% 0.008% 0.015% 0.033% Air, pH 4.2 0.003% 0.004% 0.004%0.006% 0.032% Air, pH 3.9 0.003% 0.003% 0.009% 0.019% 0.040%

[0081] TABLE 6 Numbers represent percent of Degradant 2 (w/w). HeadSpace, pH Initial Post T.S. 30° C. 40° C. 50° C.  4% O₂, pH 4.2 0.003%0.006% 0.008% 0.010% 0.017%  6% O₂, pH 4.2 0.003% 0.006% 0.008% 0.010%0.019% 10% O₂, pH 4.2 0.002% 0.006% 0.009% 0.013% 0.024% Air, pH 4.60.002% 0.005% 0.012% 0.018% 0.043% Air, pH 4.2 0.001% 0.005% 0.008%0.012% 0.042% Air, pH 3.9 0.001% 0.003% 0.013% 0.023% 0.051%

1. A pharmaceutical composition comprising a pharmaceutically effective amount of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof and water, wherein said composition contains less than about 2 parts per million of free copper ion and less than about 2 parts per million of free iron ion.
 2. A pharmaceutical composition of claim 1, wherein said composition is substantially free of free copper ion and free iron ion.
 3. A composition of claim 1, wherein said composition contains less than about 2 parts per million of any free trace metal ion.
 4. A pharmaceutical composition of claim 3, wherein said composition is substantially free of any free trace metal ion.
 5. A pharmaceutical composition of claim 1-4, further comprising a pharmaceutically acceptable buffer at a concentration effective to maintain the pH of the composition at between about 3.8 to about 5.0.
 6. A pharmaceutical composition of claim 1-4, further comprising a pharmaceutically acceptable buffer at a concentration effective to maintain the pH of the composition at between about 4.0 to about 4.5.
 7. A pharmaceutical composition of claim 14, further comprising a pharmaceutically acceptable buffer at a concentration effective to maintain the pH of the composition at between about 3.8 to about 5.0 wherein the anion of said buffer is selected from acetate, citrate, tartrate, formate and lactate.
 8. A pharmaceutical composition of claim 14, further comprising a pharmaceutically acceptable buffer at a concentration effective to maintain the pH of the composition at between about 3.8 to about 5.0 wherein the anion of said buffer is lactate.
 9. A pharmaceutical composition of claim 1-4, wherein said composition is substantially free of oxygen.
 10. A pharmaceutical composition comprising (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof, water and a pharmaceutically acceptable chelating agent at a concentration effective to chelate with trace metal ions present in said composition.
 11. A pharmaceutical composition of claim 10 wherein said chelating agent is selected from ethylenediaminetetraacetic acid, citric acid, succinic acid and tartric acid and pharmaceutically acceptable salts thereof.
 12. A pharmaceutical composition of claim 10, further comprising a pharmaceutically acceptable buffer at a concentration effective to maintain the pH of the composition at between about 3.8 to about 5.0.
 13. A pharmaceutical composition of claim 12, wherein the anion of said buffer is selected from acetate, citrate, tartrate, formate and lactate.
 14. A pharmaceutical composition of claim 10, wherein said composition is substantially free of oxygen.
 15. A pharmaceutical composition comprising (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof in an aqueous solution, wherein the percent of the degradation product, 4-hydroxybenzaldehyde, is no more than about 0.15 percent of said composition following storage at 50° C. for 12 weeks.
 16. A pharmaceutical composition of claim 15, wherein the percent of said degradation product is no more than about 0.07 percent.
 17. The pharmaceutical composition of claim 16, wherein the percent of said degradation product is no more than about 0.04 percent.
 18. A pharmaceutical composition comprising (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof in an aqueous solution, wherein the percent of the degradation product, 4-hydroxy-4-phenylpiperidine, is no more than about 0.2 percent of said composition following storage at 50° C. for 12 weeks.
 19. A pharmaceutical composition of claim 18, wherein the percent of said degradation product is no more than about 0.1 percent.
 20. A pharmaceutical composition of claim 19, wherein the percent of said degradation product is no more than about 0.05 percent.
 21. A method of preparing a pharmaceutical composition of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl )-1-propanol comprising combining a pharmaceutically effective amount of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof with a vehicle comprising water wherein said vehicle has been treated with a means to remove trace metal ions.
 22. A method of preparing a pharmaceutical composition of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol comprising: combining a pharmaceutically effective amount of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof with a vehicle comprising water to form an aqueous solution; and treating said aqueous solution with a means to remove trace metal ions.
 23. A method of treating stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, CNS degenerative diseases such as Alzheimer's disease, senile dementia of the Alzheimer's type, Huntington's disease, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychotic conditions, drug addictions, migraine, hypoglycemia, anxiolytic conditions, urinary incontinence or an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised, in a mammal, comprising administering to a mammal in need of such treatment a pharmaceutical composition of claim
 1. 